Acylthio-steroids and production thereof



r45 jcfi 3,016,386

3,016,386 ACYLTHitlSTERGlDd AND PRODUCTIUN THEREOF Taichiro Knmeno, Sumiyoshi-ku, @saka-shi, Japan, assignor to Shionogi 8: 30., Ltd, @saka-shi, Japan No Drawing. Filed Juiy 22, 1960, Ser. No. 44,514 Claims priority, application Japan Aug. 6, 1959 6 Claims. (Ci. 260-3912) This invention relates to acylthio-steroids and to methods for their preparation. More particularly, the invention concerns a novel method for the preparation of novel acylthio derivatives, of steroids, which are useful as anti-metabolites of steroidal hormones or as intermediates in the synthesis thereof.

Recently, biochemical activity of organic compounds containing sulfur has been noted and some attempts have been made to introduce an acylthio group into the steroid nucleus. For example, R. M. Dodson et a1. had reported a series of processes whereby introduction of effectivesulfur-containing groups into the steroid nucleus may be achieved.

The method of the present invention is generally appli- I cable to the A -3-oxo-steroids. The reaction of the present invention may be carried out by dissolving .A -3-oxosteroids in alkanethiolic acid, and then allowing the reaction mixture to stand at room temperature. As this reaction seems to proceed by radical mechanism, it is desirable to carry out the reaction in the presence of a catalyst, such as organic peroxide or the like. Alternatively, irradiation by ultraviolet rays may be effective for promotion of the reaction. Though the reaction is generally performed without any solvent, a suitable reaction solvent such as ether, tetrahydrofuran, dioxane, benzene, or the like may be employed.

This invention is distinguished from Dodsons report, which is most similar to the invented method at present,

as follows:

The product obtained is valuable medicinally as an antigonadotropic agent or an intermediate for the prepais approximately equal to the p'arentcompound in potency in the gonadotrophin inhibition test, and the androgenic activity of the compound is only 27 percent of the parent compound in the androgenic test. This result shows the usefulness of the product as an anti-gonadotropic agent.

in analogous manner, any of the other intermediates of the instant invention can be converted to the corresponding end-product.

The following specific examples serve to illustrate this invention, but are not intended to limit the scope of the same.

' Example 1 4 g. of 4-cholesten 3-one and 400 mg. of benzoylperoxide were dissolved in 20 ml. of ethanethiolic acid, andallowed to stand for 5 days at room temperature. Re-

moving ethanethiolic acid in vacuo, the residue was dis-' solved in ether, and washed with sodium carbonate solution thoroughly to eliminate the acid. Distilling off the solvent, the residue was chromatographed on g. of Florisil. After recovering 4-cholestene-3-one eluted with petr. ether-benzene (3:1, 2:1 and 121), the fraction eluted with benzene-ether was recrystallized from methanol to yield 200 mg. of 5a-acetylthio cholestan-3-one as flat needles, MP. -482 C.

LR. (Nujol) a: 5.81 (3-ketone); 5.92, 8.94, 9.00 (acetylthio). U.V. (EtOH) mu: 234 (e: 6000).

4 g. of l7,8-propionyloxy-4-androsten-3 -one (testosterone propionate) and 400 mgiof benzoyl peroxide were dissolvedin 5 ml. of ethanethiolic acid, and allowed to. T

stand for 7 days at room temperature.

'After the removal of the ethanethiolic acid, the residue was treated with methanol to yield750 mg. of crude crystals, M.P.' 120-140 C. Recrystallizingfrom methanol, 180 mg. of Stx-acetyIthio-17fi-propionyloxy-androstan-3 one (5a-acetylthio-dihydro-testosterone propionate) were obtained as needles, MP. l94196 vC.

l.R.' (Nujol) n: 5.78, 8.43 (propionyloxy); 5.92, 8.98, 9.21 (acetylthio). U.V. (EtOH) mu: 233 (e: 4900). [a] +35.5i3 (c: 0.774 chloroform).

Anal.-Calcd. for C H 0 S: C, 68.53; H, 8.63; S, 7.62. Found: C, 68.63; H, 8.75; S, 7.82.

I Various changes and modifications maybe made in the method of the present invention without departing from the spirit or scope thereof, and it is to be understood that the sole limitations intended are those defined in the appended claims.

Thus describing my invention, I claim:

1. 5a-acetylthio-cholestan-3-0ne.

2. Sa-acetylthiO-l7B-propionyloxy-androstan-S-one.

3. A process for the preparation of Sa-acylthio-choles- ,tan-3-one which comprises treating 4-cholesten-3-one with alkanethiolic'acid at room temperature in the presence of organic peroxide, whereby the acylthio group is introduced into the Set-position, and recovering the resultant 5ot-acyl-- thio-cho-1estan-3-one.

4. A process for the preparation of 5ot-acylthio-l7fipropionyloxy-androstan-3-one which comprises treating 17fl-propionyloxy-4-androsten 3 one with alkanethiolic acid at room temperature in the presence of organic peroxide, whereby the acylthio group is introduced into the 5 x-p0Siti0l1, and recovering the resultant 5ot-acylthio-17B- propionyloxy-androstan-3-one.

5. A process for the preparation of Sa-acetylthiocholestan-Z-one which comprises treating 4-cholesten-3- one with ethanethiolic acid at room temperature inthe 7 presence of benzoyl' peroxide, whereby the acetylthio Patented Jen n.9, 1862 group is introduced into the Set-position, and recovering the resultant 5OL-fiCfitYlthiO-Ch9165tflH-3-OI1.

6. A process for the preparation of Sa-acetyIthiO-UB- propionyloxy-androstan-S-one which comprises treating 17fi-propiony1oXy-4-andr0sten 4 3 one with ethanethiolic acid at room temperature in the presence of benzoyl peroxide, whereby the acetylthio group is introduced into the Set-position, and recovering the resultant Sa-aCetylthio- 17fi-propiony1oxy-androstan-3-one.

References Cited in the file of this patent Dodson et a1.: I.A.C.S. 81, 1224-1227, Mar. 19, 1959. 

1. 5A-ACETYLTHIO-CHOLESTAN-3-ONE. 